Background and Purpose-We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries. Methods-A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition. Results-During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group (PϽ0.001). After adjustment for baseline characteristics, adding an antiplatelet agent to warfarin increased the risk of the primary end point (relative riskϭ1.76; 95% CI, 1.05 to 2.95), and adding another antiplatelet agent to single antiplatelet agent therapy increased the secondary end point of any bleeding, including minor events (relative riskϭ1.37; 95% CI, 1.07 to 1.76). Conclusions-The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.

Background: To determine whether the use of oral antithrombotic agents before the onset of intracerebral hemorrhage (ICH) affects hematoma features and early patient outcome. Methods: A retrospective, multicenter study involving 1,006 consecutive Japanese patients (607 men, 67 ± 12 years of age) hospitalized within 24 h after the onset of nontraumatic ICH was conducted. Results: One hundred and eighty patients were taking oral antiplatelet agents (17.9%, AP group), 67 were taking warfarin (6.7%, W group), and 21 were taking both (2.1%, W + AP group). After adjustment for age, sex, and known confounders, the taking of each kind of antithrombotic therapy was independently related to cerebellar hemorrhage; the odds ratios (OR) and 95% CI, with patients taking no antithrombotic agents as the reference group, were 2.31 (1.23–4.32) for the AP group, 2.90 (1.26–6.63) for the W group, and 3.43 (1.02–11.59) for the W + AP group. Similarly, the taking of each kind of antithrombotic therapy was independently related to hematoma enlargement within the initial 24 h (OR and 95% CI: AP group, 1.92, 1.10–3.34; W group, 4.80, 2.12–10.87; W + AP group, 4.94, 1.31–18.61) and mortality at 3 weeks post-ICH (OR and 95% CI: AP group, 2.70, 1.56–4.68; W group, 2.50, 1.05–5.96; W + AP group, 9.41, 2.78–31.88). Conclusions: Prior medication with antiplatelet agents, warfarin, or both was predictive of cerebellar hemorrhage, hematoma enlargement, and early death in Japanese ICH patients.

Lipopolysaccharide (LPS), administered 72 hours before middle cerebral artery (MCA) occlusion, confers significant protection against ischemic injury. For example, in the present study, LPS (0.9 mg/kg intravenously) induced a 31% reduction in infarct volume (compared with saline control) assessed 24 hours after permanent MCA occlusion. To determine whether LPS induces true tolerance to ischemia, or merely attenuates initial ischemic severity by augmenting collateral blood flow, local CBF was measured autoradiographically 15 minutes after MCA occlusion. Local CBF did not differ significantly between LPS- and saline-pretreated rats (e.g., 34 +/- 10 and 29 +/- 15 mL x 100 g(-1) x min(-1) for saline and LPS pretreatment in a representative region of ischemic cortex), indicating that the neuroprotective action of LPS is not attributable to an immediate reduction in the degree of ischemia induced by MCA occlusion, and that LPS does indeed induce a state of ischemic tolerance. In contrast to the similarity of the initial ischemic insult between tolerant (LPS-pretreated) and nontolerant (saline-pretreated) rats, microvascular perfusion assessed either 4 hours or 24 hours after MCA occlusion was preserved at significantly higher levels in the LPS-pretreated rats than in controls. Furthermore, the regions of preserved perfusion in tolerant animals were associated with regions of tissue sparing. These results suggest that LPS-induced tolerance to focal ischemia is at least partly dependent on the active maintenance of microvascular patency and hence the prevention of secondary ischemic injury.

. Regional differences in mechanisms of cerebral circulatory response to neuronal activation. Am J Physiol Heart Circ Physiol 280: H821-H829, 2001.-Vibrissal stimulation raises cerebral blood flow (CBF) in the ipsilateral spinal and principal sensory trigeminal nuclei and contralateral ventroposteromedial (VPM) thalamic nucleus and barrel cortex. To investigate possible roles of adenosine and nitric oxide (NO) in these increases, local CBF was determined during unilateral vibrissal stimulation in unanesthetized rats after adenosine receptor blockade with caffeine or NO synthase inhibition with N G -nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole (7-NI). Caffeine lowered baseline CBF in all structures but reduced the percent increase during stimulation only in the two trigeminal nuclei. L-NAME and 7-NI lowered baseline CBF but reduced the percent increase during stimulation only in the higher stations of this sensory pathway, i.e., L-NAME in the VPM nucleus and 7-NI in both the VPM nucleus and barrel cortex. Combinations of caffeine with 7-NI or L-NAME did not have additive effects, and none alone or in combination completely eliminated functional activation of CBF. These results suggest that caffeine-sensitive and NO-dependent mechanisms are involved but with different regional distributions, and neither fully accounts for the functional activation of CBF. adenosine; nitric oxide; caffeine; 7-nitroindazole; N G -nitro-Larginine NUMEROUS STUDIES HAVE ESTABLISHED that neuronal functional activation is associated with increases in both cerebral energy metabolism and blood flow (CBF) in components of the activated neural pathway (8,18,(30)(31)(32). The increases in energy metabolism evoked by functional activation have been shown to be proportional to the increases in spike frequency in the afferent inputs to the activated areas (13, 32) and to be due mainly to activation of Na ϩ -K ϩ -ATPase activity (21, 32). The mechanisms mediating the increases in CBF during functional activation remain, however, largely undefined. A popular hypothesis proposed by Roy and Sherrington (27) was that CBF is intrinsically regulated by products of energy metabolism to meet the altered metabolic demands associated with functional activity. This hypothesis received support from subsequent findings that CBF is raised by increased CO 2 tension, lowered pH, and decreased oxygen tension, all expected consequences of increased tissue metabolism, and reduced by changes in these chemical factors in the opposite direction, to be expected with decreased metabolism (14). Since then, many other endogenous agents that affect cerebral blood vessels, e.g., nitric oxide (NO), adenosine, adenine nucleotides, K ϩ , prostaglandins, vasoactive intestinal peptide, etc., have been identified and considered as possible candidates, but not one of them, alone or in combination with others, has yet been proven to account fully or even to be essential for the enhancement of CBF by neuronal activation.Inhibition of cerebral glucose utilization by hypo...